Genetic Variant LAPTM4B:p.Cys15Trp (chr8-97776054-C-G) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_018407.6(LAPTM4B):c.45C>G(p.Cys15Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000696 in 1,436,064 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000070 ( 0 hom. )

Consequence

LAPTM4B
NM_018407.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.30

Publications

0 publications found

Variant links:

Genes affected

LAPTM4B (HGNC:13646): (lysosomal protein transmembrane 4 beta) Enables ceramide binding activity; enzyme binding activity; and phosphatidylinositol bisphosphate binding activity. Involved in several processes, including negative regulation of macromolecule metabolic process; regulation of lysosomal membrane permeability; and regulation of lysosome organization. Located in several cellular components, including endosome; lysosomal membrane; and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

LAPTM4B links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.837

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAPTM4B	NM_018407.6 link	c.45C>G	p.Cys15Trp	missense_variant	Exon 1 of 7	ENST00000521545.7	NP_060877.4	Q86VI4-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
LAPTM4B	ENST00000521545.7 link	c.45C>G	p.Cys15Trp	missense_variant	Exon 1 of 7	1	NM_018407.6	ENSP00000428409.1	Q86VI4-2
LAPTM4B	ENST00000445593.6 link	c.318C>G	p.Cys106Trp	missense_variant	Exon 1 of 7	1		ENSP00000402301.2	Q86VI4-3
LAPTM4B	ENST00000619747.1 link	c.318C>G	p.Cys106Trp	missense_variant	Exon 1 of 7	1		ENSP00000482533.1	Q86VI4-3
LAPTM4B	ENST00000517924.5 link	c.45C>G	p.Cys15Trp	missense_variant	Exon 1 of 5	5		ENSP00000429868.2	H0YBN1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000945

AC:

AN:

211554

AF XY:

0.0000170

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000214

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000696

AC:

AN:

1436064

Hom.:

Cov.:

AF XY:

0.00000420

AC XY:

AN XY:

714694

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30260

American (AMR)

AF:

0.00

AC:

AN:

43352

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25356

East Asian (EAS)

AF:

0.00

AC:

AN:

36062

South Asian (SAS)

AF:

0.00

AC:

AN:

85158

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47726

Middle Eastern (MID)

AF:

0.000362

AC:

AN:

5528

European-Non Finnish (NFE)

AF:

0.00000544

AC:

AN:

1103140

Other (OTH)

AF:

0.0000336

AC:

AN:

59482

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.00000835

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 26, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.318C>G (p.C106W) alteration is located in exon 1 (coding exon 1) of the LAPTM4B gene. This alteration results from a C to G substitution at nucleotide position 318, causing the cysteine (C) at amino acid position 106 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.92

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

-0.030

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.29

.;.;.;T

Eigen

Uncertain

0.40

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.93

D;.;D;D

M_CAP

Pathogenic

0.39

MetaRNN

Pathogenic

0.84

D;D;D;D

MetaSVM

Benign

-0.44

PhyloP100

3.3

PrimateAI

Pathogenic

0.90

PROVEAN

Pathogenic

-8.7

.;D;D;.

REVEL

Uncertain

0.46

Sift

Uncertain

0.0010

.;D;D;.

Sift4G

Pathogenic

0.0010

D;D;D;D

Vest4

0.92

MVP

0.75

MPC

1.1

ClinPred

1.0

GERP RS

4.3

PromoterAI

-0.044

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.91

gMVP

0.97

Mutation Taster

=6/94

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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8-97776054-C-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over